New Analysis Calls Into Question Validity of PIVOT Findings

Pam Harrison

March 27, 2018

COPENHAGEN, Denmark —  Men involved in the PIVOT (Prostate Cancer Intervention versus Observation Trial) study — results of which underpin much of the policy regarding prostate cancer management in the United States today — do not represent "real-world" patients in the United States, a new analysis suggests.

As such, the PIVOT study's finding that there is no mortality benefit from radical prostatectomy over that achieved with active surveillance alone does probably not apply to patients with prostate cancer in the United States, investigators are suggesting.

"The direct clinical implication of the PIVOT study is that we should abandon surgery in virtually all prostate cancer patients and limit our management to observation," Firas Abdollah, senior urology fellow at the Henry Ford Hospital in Detroit, Michigan, said in a statement.

"However, in most experts' opinion, this would result in a significant increase in the number of men with metastatic prostate cancer and in those who will succumb to the disease," he added.

"What this really means is that we need to wait until a definitive study can show the relative benefits of intervention versus observation," Abdollah concluded.

The new analysis was presented here at the European Association of Urology (EAU) 2018 Congress.

Investigators analyzed 3 US cancer databases to compare men diagnosed with prostate cancer in the United States at different time points to those enrolled in PIVOT.

Data were taken from the Surveillance, Epidemiology, and End Results (SEER) population-based registry between 2000 and 2004; the National Cancer Database (NCDB) between 2004 and 2005; and the Prostate, Lung, Colorectal and Ovarian (PLCO) trial between 1993 and 2001.

"We included only men undergoing surgery or observation who satisfied the inclusion criteria of PIVOT," investigators observe. Patients in PIVOT had localized prostate cancer and a median prostatic-specific antigen value of 7.8 ng/mL at the time of diagnosis.

Some 2847 men from PLCO, 60,080 men from SEER, and 63,303 men from NCDB were included in the current analysis.

Mean Age

In the PIVOT trial, the mean age of participants was 67 years.

This was older than the mean age for men in the three databases analyzed: 65.8 years for those participating in PLCO, 61.3 years for those registered in SEER, and 60.2 for those registered in the NCDB (P < .001).

Moreover, well over 90% of men in both PLCO and the NCDB had a Charlson comorbidity index of 0.

This compared to only 56% of men in PIVOT (P < .001) — indicating that men in PIVOT were both older and sicker than men in the three US databases analyzed, Abdollah suggested. There are no comorbidity data in the SEER database.

More important, the overall mortality in the PIVOT study, at 64% over 12.7 years of follow-up, was three to eight times higher than mortality rates documented in the three US cancer databases.

For example, overall mortality rates were 8% for patients involved in the PLCO study, 9% for men registered in the NCDB, and 23% for those registered in SEER over a follow-up interval of 7.5 to 12.3 years.

"Interestingly, within SEER, the mean age at diagnosis for men who were not recommended surgery was 65.1 years, with overall mortality [at] 50% over a median follow-up of 12.5 years," researchers observe, suggesting that overall survival rates in PIVOT were worse even when compared to those in men within the SEER database who did not undergo definitive treatment.

The findings from this analysis suggest that there was a sampling bias in PIVOT; they highlight the lack of generalizability, and thus external validity, of the PIVOT findings to men diagnosed with clinically localized prostate cancer in the United States.

Commenting on the findings in an EAU statement, Hein van Poppel, MD, professor of surgery, University of Leuven in Belgium, noted that in the first PIVOT analysis carried out in 2012, it was clear that radical prostatectomy had an advantage over active surveillance in patients with a poor prognosis.

"Now, this evaluation of the dataset used in PIVOT suggests that the balance needs to change even in early-stage prostate cancer patients," van Poppel commented.

"And we need to seriously re-evaluate the PIVOT study before taking implementation any further," he added.

The study received no external funding. Abdollah reports serving as a consultant/advisor to GenomeDx Biosciences. Van Poppel has disclosed no relevant financial relationships.

European Association of Urology (EAU) 2018 Congress. Abstract 162. Presented March 16, 2018.

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